For Treating Depression Potential Target Identified

A novel molecular mechanism responsible for the most important symptom of major depression: anhedonia was found by scientists. Anhedonia is the loss of the ability to experience pleasure.

For Treating Depression Potential Target Identified

While the Stanford University School of Medicine study was conducted in mice, the brain circuit involved in this newly elucidated pathway is largely identical between rodents and humans, upping the odds that the findings point toward new therapies for depression and other disorders.

Additionally, opinion leaders hailed the study's inventive methodology, saying it may offer a much sounder approach to testing new antidepressants than the methods now routinely used by drug developers.

Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences, is the senior author of the new study, which reveals a novel drug target by showing how a hormone known to affect appetite turns off the brain's ability to experience pleasure when an animal is stressed.

This hormone, melanocortin, signals to an ancient and almost universal apparatus deep in the brain called the reward circuit, which has evolved to guide animals toward resources, behaviours and environments - such as food, sex and warmth - that enhance their prospects for survival.

Malenka's team decided to use chronically stressed mice to explore the activity of a naturally occurring molecule, melanocortin.

"A few scattered studies had suggested that chronic stress increased melanocortin levels in the brain," he said. "And it was known that stressed animals have heightened numbers of receptors for melanocortin in the nucleus accumbens," a key region of the reward circuit.

If this all-important circuit is working properly, it doles out pleasure when an animal achieves a desirable goal or experiences rewarding stimuli, such as food or sex. If it's not working properly, anhedonia is the result.

Malenka's team subjected mice to chronic stress by confining them, for three to four hours a day, in small conical tubes with holes in them for air flow over a period of eight days. This stressful confinement clearly reduced the mice's preference for sugar water over plain water. (The animals also lost about 5-10 percent of their body weight, a frequent depression symptom.)

The scientists found that both chronic stress and the direct administration of melanocortin diminished the signaling strength of some of the tiny electrochemical contacts, known as synapses, on a set of nerve cells in the nucleus accumbens that contain receptors for melanocortin.

When these receptors were removed using a sophisticated laboratory trick, the same stressful confinement no longer caused changes in those nerve cells' synapses. Simultaneously, despite the weeklong stressful experience, the mice's sugar preference was returned to normal. Plus, the animals no longer lost weight.

To test whether preventing these stress-elicited biochemical changes in the brain also reduced the effects of stress on the mice's behavioral response to things besides food and sugar water, the research team substituted cocaine for sugar. They got the same constellation of results with cocaine as they had in their earlier experimentation - further strong evidence that the chronic-stress-induced changes in the brain due to melanocortin action cause an animal to lose its ability to experience pleasure.

Importantly, Malenka and his associates also demonstrated that the brain circuit transmitting melanocortin's morose message to the reward circuitry operates independently of the circuitry responsible for making a mouse give up the ghost when the game gets too tough.

Manipulating the melanocortin-associated pathway in the nucleus accumbens had no effect on the mice's performance in the forced-swim test. The stressed mice gave up just as easily when the melanocortin receptors in their nucleus accumbens were depleted as when they weren't.

By looking at the circuits and mechanisms underlying anhedonia, Malenka and his associates thus avoided a pitfall of research on mental diseases, said Hyman.

The melanocortin pathway is already of interest to drug companies, Malenka said, because it appears to be involved in appetite disorders. So companies already have melanocortin mimics and inhibitors at their disposal that could be used in clinical tests to determine whether managing patients' melanocortin signaling relieves anhedonia.

This could have implications beyond treatments for depression because anhedonia manifests in other neuropsychiatric syndromes, such as schizophrenia, as well as in terminally ill people who have given up hope.

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